Tumor necrosis factor (TNF) is a macrophage/monocyte-derived inflammatory cytokine whose dysregulation has been shown by us and others to play an important role in the pathophysiology of several forms of liver injury including that observed in alcoholic liver disease (ALD). TNF also has been postulated to play a pivotal role in the metabolic complications and wasting of Acquired Immunodeficiency Syndrome (AIDS). There are great similarities between the metabolic abnormalities/complications of AIDS and ALD including anorexia, cachexia, immune suppression, hypoalbuminemia, increased acute phase reactants and edema, to name only a few. We have demonstrated increased plasma TNF, increased monocyte TNF production, and increased hepatic immunohistochemical staining for TNF in patients with ALD. Mitochondrial dysfunction/structural damage is an early event in ALD, and it has also been postulated to play a role in organ dysfunction in AIDS. TNF, per se, causes mitochondrial dysfunction/damage including inhibition of respiration, superoxide generation, and ultimately cell injury. Impairment of normal mitochondrial respiration markedly enhances TNF cytotoxicity. TNF mediated cytotoxicity is thought to be an oxidant injury, and TNF induction of the mitochondrial antioxidant manganous superoxide dismutase (MnSOD) is an endogenous protective mechanism to prevent ongoing TNF cytotoxicity. Regulation of cytokines such as TNF has become a focal point for therapeutic intervention in many diseases including ALD and AIDS. NFkappaB is a transcription factor for several cytokines including TNF and for the HIV virus. NFkappaB is activated by reactive oxygen intermediates, and this activation can be blocked by antioxidants such as vitamin E (Vit E) and glutathione (GSH)-enhancing agents in certain transformed cell lines. It is our working hypothesis that TNF plays an etiologic role in many of the clinical/biochemical abnormalities observed in ALD and AIDS. We postulate that chronic alcohol abuse and HIV infection cause increased gut permeability and endotoxemia, depletion of many nutrient antioxidants (e.g., GSH, Vit E), generation of reactive oxygen intermediates, activation of NFkappaB, increased TNF production, mitochondrial dysfunction with mitochondrial GSH depletion, and ultimately wasting and organ dysfunction including liver injury. The overall research goals of this laboratory are to further define mechanisms and modulatory pathways whereby cytokines, such as TNF, induce metabolic disturbances/liver injury in ALD and in AIDS, with the ultimate goal being development of specific "anticytokine" therapy for ALD and for AIDS. The specific objectives in this proposal (initially performed in ALD patients) are to: 1) Evaluate dysregulated cytokine (TNF, IL-8) production in ALD, the role of antioxidant status and NFkappaB activation in modulating this cytokine production and the role of "anticytokine" therapy; 2) Determine the role of mitochondrial dysfunction/protection in alcohol/TNF-mediated hepatotoxicity; and 3) Determine whether unique forms of antioxidant therapy attenuate dysregulated TNF production and mitochondrial dysfunction in patients with ALD. This research spans the spectrum from molecular cellular studies to applied human investigations, with the ultimate goal being improved knowledge and therapy for these two devastating disease processes with overlapping metabolic complications.